Liraglutide mitigates LPS-induced osteoclastogenesis and bone loss by downregulating macrophage TNF-α expression

Inflammatory bone destruction, a hallmark of conditions like periodontitis and rheumatoid arthritis, involves excessive osteoclast activity leading to bone loss. Current treatments often target osteoclasts directly or broadly suppress inflammation, but can have systemic side effects. Lipopolysaccharide (LPS), a bacterial endotoxin, is a potent inducer of inflammation and osteoclastogenesis, making it a relevant model for inflammatory bone disease. Glucagon-like peptide-1 receptor (GLP-1R) agonists like Liraglutide are known for their anti-diabetic and anti-obesity effects, but emerging evidence suggests broader anti-inflammatory properties, prompting investigation into their potential in bone health.

Researchers investigated Liraglutide's effect on inflammatory bone loss using both in vivo and in vitro models. In mice, Liraglutide was co-administered with LPS directly to the calvaria regions. The primary endpoints included osteoclast numbers and bone resorption areas, compared against an LPS-alone control group. In vitro experiments utilized various cell types: RANKL-induced osteoclastogenesis assays assessed direct effects on osteoclast formation, TNF-α-induced osteoclastogenesis assays evaluated direct inhibition, and LPS-stimulated osteoblasts were used to check RANKL expression. Crucially, LPS-stimulated macrophages were cultured to determine Liraglutide's impact on TNF-α mRNA expression.

In the in vivo model, co-administration of Liraglutide with LPS in mice led to a markedly reduced number of osteoclasts and significantly smaller bone resorption areas compared to the LPS-alone group. This protective effect was accompanied by notably lower expression levels of receptor activator of NF-κB ligand (RANKL) and tumor necrosis factor (TNF)-α mRNA in the Liraglutide + LPS group. In vitro studies provided critical mechanistic insights: Liraglutide demonstrated no direct inhibitory effect on RANKL-induced osteoclastogenesis, nor did it directly suppress TNF-α-induced osteoclastogenesis. Furthermore, Liraglutide had no direct inhibitory effect on LPS-stimulated RANKL expression in osteoblasts. These findings collectively point to an indirect mechanism. > The most significant finding was that Liraglutide effectively suppressed TNF-α mRNA expression in macrophages that were stimulated by LPS, suggesting its bone-protective role is mediated through modulation of macrophage inflammatory responses rather than direct action on osteoclasts or osteoblasts.